Mixtures of polymers for medical use

ABSTRACT

Polymer compositions of a mixture of vinyl chloride polymer and polyurethane with tertiary amine and/or ammonium groups and heparin.

This is a division of application Ser. No. 417,323, filed Sept. 13,1982, now U.S. Pat. No. 4,394,462 which in turn is a division ofapplication Ser. No. 103,894, filed Dec. 17, 1979, now U.S. Pat. No.4,408,026.

The present invention relates to polymers which can be converted intoshaped articles and can be used in the medical field.

It is known that polymers are widely and increasingly used in themedical field for a very large number of application; thus, they areused for all the materials which are to be in contact with blood orother biological liquids; more precisely, the need for such products(referred to as "medical plastics") in the manufacture of storageflasks, blood bags, tubes, probes, cannulae, catheters and all theequipment which is useful either in blood transfusion operations andperfusion operations or in artificial kidney and lung systems, may bementioned. Polymers with similar properties are sought in other fieldsin which it is also necessary to bring polymers into contact with abiological liquid, for example milk in the field of nutrition.

The use of polymers based on vinyl chloride has developed fairly wellbecause of various advantages associated with the nature of theseproducts (in particular their moderate cost); unfortunately, polyvinylchloride itself is not sufficiently flexible, and, if it is desired toplasticise it, the known plasticisers, in particular phthalates, havemuch too great a tendency to give rise to the phenomena of exudation andespecially of leaching, which is disadvantageous because of the risk ofaccumulation of plasticiser in the biological liquid or the human body.The leaching of polyvinyl chloride plasticisers takes place simply byextraction of these plasticisers when the polymer is in contact withbiological liquids.

One object of the present invention is to provide polymers which can beused in prolonged contact with biological liquids, in particular blood,plasma, milk and protein solutions.

A further object of the invention is to provide plastic polymers basedon vinyl chloride.

A further object of the invention is to provide polymers plasticisedwith non-leachable plasticisers.

A further object of the invention is to provide polymers which have beenheparin-treated either in bulk or after they have been shaped.

A further object of the invention is to provide heparin-treated polymerswhich only slowly release the heparin which they contain.

The invention therefore relates firstly to polymer compositions whichare characterised in that they comprise a mixture of vinyl chloridepolymer and of polyether-urethane with tertiary amine and/or ammoniumgroups.

The respective proportion of the constituents in the mixture can varywithin wide limits; for example, the proportion of polyether-urethanecan be 1 to 99% by weight, relative to the total mixture. However, thisproportion of polyurethane is preferably between 20 and 60%.

Vinyl chloride polymers which are particularly used are the homopolymersand copolymers having at least 60% by weight of radicals derived fromvinyl chloride (that is to say of chloroethylene units --CHCl--CH₂ --).As copolymers which can more especially be used, there may be mentionedthe copolymers of vinyl chloride and vinyl esters, in particular vinylacetate. Of course, it is also possible to use terpolymers derived fromvinyl chloride, a non-ionic and non-ionisable monomer (such as vinylesters) and an ionic or ionisable monomer (such as maleic acid); theproportion of this latter monomer is generally limited to 20%,preferably to 8%, by weight, relative to all the monomers in the polymerin question.

As polyether-urethanes with tertiary amine and/or ammonium groups, theremay be used either polyether-urethanes in which the amine and/orammonium groups are located in a branch of the main polymer chain, orpolyether-urethanes in which the amine and/or ammonium groups are in themain polymer chain.

The polyether-urethanes, with amine and/or ammonium groups, which areused in the invention are preferably polyurethanes derived frompolyethers with oxyalkylene groups (it being possible for thisoxyalkylene group to be substituted).

In the following text, the letters n, m, p and q are used to denote,respectively:

n--the number of milliequivalents of oxyethylene units --O--CH₂ --CH₂ --per 100 g of polyurethane;

m--the number of milliequivalents of tertiary amine groups, which may ormay not be salified, per 100 g of polyurethane. The tertiary aminegroups, when they are salified, constitute tertiary ammonium groups; thepolyurethanes, with ammonium groups, which are used in the inventiontherefore have either tertiary ro quaternary ammonium groups;

p--the number of milliequivalents of quaternary ammonium groups per 100g of polyurethane; and

q--the number of milliequivalents of ionic groups per 100 g of vinylchloride polymer.

The nitrogen-containing polyether-urethanes used in the invention andthe polymer compositions derived therefrom are therefore such that theypreferably satisfy the following relationships:

    m+p≧0.5

    p+q≧(n/100)-2.5

The nitrogen-containing polyether-urethanes used in the inventionusually comprise a plurality of repeat units of the formula:

    --A--NH--CO--O--B--O--CO--NH--                             (I)

and of repeat units of the formula:

    --A--NH--CO--Z--NH--                                       (II)

in which formulae:

B is the divalent radical in a macrodiol of the polyether type, of theformula: HO--B--OH,

A is the divalent radical in an aliphatic and/or cycloaliphatic and/oraromatic diisocyanate of the formula: O═C═N--A--N═C═O, and

Z is a valence bond or a divalent radical such as: --NH--NH--CO--,--NH--CH₂ --CO--NH--NH--CO--, --NR₂ --D--NR₃ --CO-- or --O--M--O--CO--;R₂, R₃ and M are such that NHR₂ --D--NHR₃ is a primary or secondarydiamine and HO--M--OH is a diol.

The units of the formulae I and II are attached to one another in such away that a terminal carbon atom of one unit is bonded to a terminalnitrogen atom of another unit.

In the invention, the amine and/or ammonium groups can therefore befound, in particular, in the radicals B, A, D or M, but preferably B.

The polyether-urethanes are prepared in the usual manner; the mostcommon process consists in preparing a macrodiisocyanate from amacrodiol and a diisocyanate; the macrodiol used is preferably apoly-(oxyalkylene)-glycol, in particular a poly-(ethylene)-glycol or apoly-(propylene)-glycol. The diisocyanate used is preferably1,6-diisocyanatohexane, diisocyanatotoluenes,bis-(isocyanatocyclohexyl)-methanes or propanes andbis-(isocyanatophenyl)-methanes or propanes.

These macrodiisocyanates are then coupled by means of coupling agentssuch as water, hydrazine, aminoacetic acid hydrazide, diamines or diols.

Most frequently, the polyurethane is prepared from reagents whichcomprise a tertiary amine group either in the macrodiol, or in thediisocyanate, or in the coupling agent. Once the polyurethane has beenprepared, the tertiary amine group can be quaternised and this thereforeproduces a polyurethane with tertiary amine and/or ammonium groups.

If, according to a preferred embodiment, a polyurethane is preparedwhich has amine and/or ammonium groups located in the polyether(preferably polyoxyalkylene) part of the polyurethane macromolecule,this polyurethane is prepared from a macrodiol containing a tertiaryamine group. Thus, according to a variant which is convenient to carryout, this macrodiol is prepared from diols and/or an alkylene oxide andfrom a diol with a tertiary amine group, such as, for example,alkylbis-(hydroxyalkyl)-amines, in particular N-ethyldiethanolamine.

Polyether-urethanes with ammonium groups are known from GermanApplication DOS 2,642,616 and from U.S. Pat. Nos. 3,655,814, 3,755,218and 3,853,804.

The compositions, according to the invention, which have not beenheparin-treated are generally soluble in solvents for vinyl chloridepolymers, in particular dimethylformamide (DMF), tetrahydrofurane (THF)and also ketones in the case of compositions containing vinyl chloridecopolymers.

It is therefore possible to prepare these compositions, and to producethe shaped articles based on these compositions, according to theinvention, by evaporating solutions of these compositions; it is alsopossible to obtain shaped articles comprising a support covered withcompositions according to the invention, by coating a shaped articlewith any material using a liquid coating layer, and then by evaporatingthis layer, the said liquid coating layer consisting of solutions ofcompositions according to the invention. A process of this type isparticularly suitable for coating the inside of tubes (in particularcatheters) but, of course, shaped articles of quite a different formfrom that of tubes, such as, for example, containers, plane surfaces andthe like, may be considered.

It is also possible to obtain shaped articles from a paste which isproduced using compositions, according to the invention, containing ablowing agent or an insufficient amount of solvent to dissolve the totalamount of the compositions, this mixture of composition and solvent orblowing agent being extruded.

The solvent or blowing agent used must be a solvent or blowing agentboth for the vinyl chloride polymer and for the polyurethane with amineor ammonium groups, or alternatively a blowing agent for the mixture ofthe two polymers combined. Dimethylformamide may be mentioned as thesolvent which can be used. In certain cases, it is possible to uselighter and more volatile solvents, such as, for example, acetone, whichmakes it possible to remove this solvent more easily in order to obtaina composition, according to the invention, in the dry state. When usingpolyurethanes coupled to ethylene glycol (HO--M--OH mentioned above) andcopolymers of vinyl chloride and vinyl acetate, these light solvents canthen be used. The pastes based on compositions according to theinvention can generally be extruded at a fairly low temperature (below100° C.).

The materials or shaped articles according to the invention, whichconsist of compositions according to the invention, have an improvedflexibility (compared with the corresponding material withoutpolyurethane), even at ambient temperature; they also have goodantistatic properties; they exhibit the advantage of avoiding the use ofplasticisers which can exude or leach in contact with biological orphysiological liquids. Since the vinyl chloride polymers and thepolyether-urethanes with amine and/or ammonium groups are generallycompatible, especially when they have been chosen in accordance with theindications given above, the materials or articles which are derivedfrom the compositions according to the invention (in particular thepreferred compositions) generally have good mechanical properties andgood transparency; moreover, they also have a good compatibility withblood. Their nature enables them to be employed very conveniently. Theirpermeability to steam renders them of value in many applicationsrequiring this property.

The invention also relates to heparin-treated compositions based onvinyl chloride polymer. The compositions are characterised in that theycomprise a vinyl chloride polymer, a polyurethane with an ammoniumgroup, preferably a quaternary ammonium group, and heparin.

In these heparin-treated compositions, the relative proportions of vinylchloride polymer and of polyurethanes are the same as those indicatedabove for the compositions which have not been heparin-treated, butthese polymers are preferably chosen so that p₁ -q₁ >0, p₁ being theproduct of p multiplied by the percentage by weight of thepolyether-urethane in the mixture, divided by 100, and q₁ being theproduct of q multiplied by the percentage by weight of the vinylchloride polymer, with ionic sites, in the mixture, divided by 100.

As regards the proportion by weight of heparin, it is usually between0.5 and 35% by weight, relative to all the polymers, and preferablybetween 1 and 15%.

In the compositions according to the invention and in the followingtext, when the term heparin is used, it is understood that this termincludes the modified heparin forms, for example its salts.

The heparin-treated compositions according to the invention can beobtained by similar processes to those already described for thecompositions which have not been heparin-treated. However, since heparinis more generally only slightly compatible or incompatible with polymersbased on vinyl chloride alone, it is recommended to introduce theheparin together with, or in the presence of, the polyurethane withammonium sites, into the vinyl chloride polymer. Thus, according to anadvantageous embodiment, a solution of vinyl chloride polymer is mixedwith a solution of heparin and of polyurethane, the two solvents for thetwo solutions being similar or at least miscible. According to anotheradvantageous embodiment, a solution of heparin is added to a solution ofa mixture of polyurethane+vinyl chloride polymer. A particularlyadvantageous process for the preparation of heparin-treated compositionsaccording to the invention, and in particular of shaped compositions,consists in producing a paste and in shaping this paste, for example byextrusion. The paste can be obtained by mixing the constituents with aninadequate amount of solvents to obtain a solution. It is also possibleto obtain a paste by partially removing the solvent from a solution. Inorder to solubilise the heparin or the mixtures of heparin+polyurethanewith amine and/or ammonium groups, mixtures of water anddimethylsulphoxide, or of water and diethylene glycol, or of water anddimethylformamide, are preferably used. In order to produce pastes ofheparin-treated compositions according to the invention, a solvent orblowing agent for these compositions is advantageously used, for exampledimethylformamide or mixtures of water+dimethylformamide or ofwater+diethylene glycol or of water+dimethylsulphoxide.

With the heparin-treated compositions according to the invention, it isfairly advantageous to employ them with a volatile solvent (for exampleacetone) in order to be able to evaporate this solvent off withoutadversely affecting the heparin (in particular by degradation). Asindicated above, the compositions, according to the invention, which arederived from vinyl chloride copolymers and from polyurethanes coupled toethylene glycol are particularly suitable for the use of a volatilesolvent in the production of pastes which can be extruded.

In order to obtain a paste of this type, it is generally advantageous tostart by forming a solution of the three constituents of the mixture, soas to obtain a very homogeneous mixture, and then, after having removedthe solvent, for example by precipitation with a nonsolvent, to add thevolatile solvent producing the paste. The preferred volatile solvent isacetone. As the solvent for the heparin-treated ternary mixture, it ispreferred to use mixtures of water/aprotic polar solvent, in particularwater/DMF, water/DMSO or water/DEG (DMF=dimethylformamide,DMSO=dimethylsulphoxide and DEG=diethylene glycol).

This process can be modified by preparing the first solution of theconstituents of the mixture with only the polyurethane and the heparin;in this case, the addition of the vinyl chloride polymer does not haveto take place until later, by malaxating all three constituents of themixture in the pasty state and in the presence of a volatile solvent.

The heparin-treated compositions according to the invention possess aparticularly good compatibility with blood and they also have a verygood anti-thrombogenic action, in particular because of the very slowleaching of the heparin. Their use for producing articles which are tobe employed in contact with blood (tubes, blood bags, artificial vesselsand catheters) is therefore particularly recommended. Theheparin-treated compositions which can be employed in the form of apaste, and especially in the form of a paste using a volatile solvent,are preferred.

Although, in the above text, consideration has only been given tocompositions which have been heparin-treated in bulk, the invention alsorelates to shaped articles, based on vinyl chloride polymers and onpolyurethane containing ammonium sites, preferably quaternary ammoniumsites, which have been heparin-treated on the surface. In this case, theamounts of heparin used are greatly reduced.

The following examples, which are given without implying a limitation,illustrate the invention and show how it can be put into effect.

EXAMPLE 1 Preparation of Unquaternised Polyurethane

333 g of N-ethyldiethanolamine and 8.32 g of potassium hydroxide areintroduced into a 7,500 cm³ autoclave provided with a nitrogenatmosphere and equipped with a stirring system; the mixture is heated at95° C. until the solid has completely dissolved. After cooling, thereaction mixture is dehydrated at 80°-82° C. under an absolute pressureof 13 mm Hg, the temperature is then raised to about 111° C. andpropylene oxide is injected, the pressure being kept at between 4 and 5bars. The amount of propylene oxide introduced after 8 hours is: 2,480g; the reaction mixture is kept at this temperature for a further 2hours and the unreacted propylene oxide (120 g) is then removed byvacuum distillation. The polyether thus obtained contains 0.936milliequivalent/gram of tertiary nitrogen. This polyether is neutralisedby adding hydrochloric acid until the pH is 6-7, the reaction mixture isthen dehydrated by heating at 80° C. under an absolute pressure of 1 to2 mm Hg and the potassium chloride formed is filtered off.

422.5 g or 4,4'-diisocyanatodiphenylmethane are added all at once, underan inert atmosphere, to 930.7 g of this salified polyether, which hasbeen heated to 80° C., and the mixture is kept at this temperature for45 minutes, whilst stirring. The resulting macrodiisocyanate is cooledand dissolved in 750 cm³ of dimethylformamide.

A solution of 37.6 g of aminoacetic acid hydrazide in 1,740 g ofdimethylformamide is then prepared by heating to 60° C. This solution iscooled, 1,015 g of the previously prepared macrodiisocyanate solutionare introduced therein, in the course of 1 hour 45 minutes, and themixture is then diluted by adding 1,890 g of dimethylformamide. Thepolyurethane solution thus obtained is poured slowly, and whilststirring vigorously, into a mixture of 8 kg of ice and 24 kg of watercontaining 128 g of sodium hydroxide, in order to precipitate thepolymer. The latter is filtered off, washed with water until thewashings are neutral, dried in vacuo at 40° C. and then dried toconstant weight over phosphorous pentoxide at ambient temperature. 682 gof polyurethane, containing 0.583 milliequivalent/g (meq/g) of tertiarynitrogen (acidimetric determination), are thus obtained.

Preparation of the Quaternised Polyurethane

256 g of the polyurethane described above are dissolved in 1,344 g ofdimethylformamide, and 85 g of methyl iodide are added to this solution.The mixture is stirred for 15 minutes at ambient temperature and thenfor 9 hours 30 minutes at 46° C. After cooling, it is run into a mixtureof 7.5 kg of ice and 25 kg of water, whilst stirring vigorously; theprecipitated polymer is filtered off, washed with water and then withmethanol and dried to constant weight as above. The degree ofquaternisation, determined by acidimetry, is 100%. The polymer contains0.538 milliequivalent of quaternary ammonium per gram (meq/g).

EXAMPLE 2 Preparation of Unquaternised Polyurethane

300 g of a polyoxyethylene glycol (marketed under the trademark CARBOWAX1,500), having a molecular weight of 1,500, are introduced into a 1liter reactor provided with a nitrogen atmosphere and equipped with astirring system and a reflux condenser. The glycol is melted and thereaction mixture is then dehydrated at 100° C. under an absolutepressure of 1 mm Hg. Atmospheric pressure is re-established byintroducing nitrogen and the temperature is lowered to 80° C. 0.4 g ofmalonitrile is introduced and 100 g of 4,4'-diisocyanatodiphenylmethaneare then introduced 15 minutes later. The temperature of the reactionmixture is kept at 80° C. for 3 hours. The resulting macrodiisocyanateis cooled and dissolved in 250 cm³ of dimethylformamide.

A solution of 23.7 g of aminoacetic acid hydrazide in 1,250 g ofdimethylformamide is then prepared. This solution is cooled and amixture of 258 g of a 65% strength solution, in dimethylformamide, ofthe macrodiisocyanate prepared in accordance with Example 1, and of 578g of a 63% strength solution, in dimethylformamide, of themacrodiisocyanate described above at the start of this Example 2, isthen run in, in the course of 4 hours. The copolyurethane solution thusobtained is poured slowly, and whilst stirring vigorously, into 30liters of water containing 600 g of sodium chloride and 120 g of sodiumhydroxide, at +5° C., in order to precipitate the polymer. The latter isfiltered off, washed with water until the washings are neutral and untilthe chloride ions have disappeared, dried in vacuo at 40° C. and thendried to constant weight over phosphorus pentoxide at ambienttemperature. 460 g of copolyurethane, containing 0.189 milliequivalent/gof tertiary nitrogen and 1,124 meq of oxyethylene units per 100 g ofpolyurethane, are thus obtained.

Preparation of the Quaternised Copolyurethane

330 g of the copolyurethane which has just been prepared in this way,and 3,300 cm³ of acetone, are introduced into a 5 liter reactor equippedwith a stirring system. 19.7 g of methyl iodide are introduced, under anitrogen atmosphere, the reactor is stoppered and the mixture is stirredfor 20 hours at ambient temperature. The polymer is filtered off, washedwith acetone and then with ether and dried to constant weight as above.The degree of quaternisation is 100%. The polymer contains 0.184milliequivalent/g of quaternary ammonium and 1,094 meq of oxyethyleneunits per 100 g of polyurethane.

EXAMPLE 3 Preparation of Unquaternised Polyurethane

16.7 g of ethylene glycol, 0.4 g of dibutyltin dilaurate and 950 g ofdimethylformamide are introduced into a 5 liter reactor provided with anitrogen atmosphere and equipped with a stirring system and a refluxcondenser. The mixture is stirred and 792 g of a 55% strength solution,in dimethylformamide, of the macrodiisocyanate prepared in accordancewith Example 1 are run in, in the course of one hour. The temperature ofthe reaction mixture is raised to 70°-75° C. in the course of one hourand the addition of the macrodiisocyanate solution is terminated slowly.The polyurethane solution thus obtained is poured, whilst stirringvigorously, into 20 liters of water containing 400 g of sodium chlorideand 80 g of sodium hydroxide, at +5° C., in order to precipitate thepolymer. The latter is filtered off, washed with water until thewashings are neutral and the chloride ions have disappeared, dried invacuo at 40° C. and then dried to constant weight over phosphoruspentoxide at ambient temperature. 450 g of polyurethane, containing0.599 milliequivalent/g of tertiary nitrogen, are thus obtained.

Preparation of Quaternised Polyurethane

The unquaternised polyurethane prepared above is quaternised inaccordance with the technique described in Example 1. The resultingpolymer contains 0.561 meq/g of quaternary ammonium. Of course, the tinsalts are removed by precipitating the polymer in a non-solvent which,however, is a solvent for the tin salts.

EXAMPLE 4 Preparation of Unquaternised Polyurethane

32.6 g of ethylene glycol, 0.97 g of dibutyltin dilaurate and 2,267 g ofdimethylformamide are introduced into a 5 liter reactor provided with anitrogen atmosphere and eqipped with a stirring system and a refluxcondenser.

90% of a mixture containing 676.8 g of a 47% strength solution, indimethylformamide, of a macrodiisocyanate prepared in accordance withExample 1, and 1,144 g of a 54% strength solution, in dimethylformamide,of a macrodiisocyanate prepared in accordance with the techniquedescribed in the first paragraph of Example 2, is run into this solutionin the course of 1 hour.

The temperature of the reaction mixture is raised to 70°-75° C. in thecourse of 1 hour, the addition of the solution of the twomacrodiisocyanates is terminated slowly and a solution of 26 g of4,4'-diisocyanatodiphenylmethane in 80 g of dimethylformamide is thenadded to the reaction medium. The copolyurethane solution thus obtainedis poured, whilst stirring vigorously, into 50 liters of watercontaining 1,000 g of sodium chloride and 200 g of sodium hydroxide, at+5° C., in order to precipitate the polymer. The latter is filtered off,washed with water until the washings are neutral and the chloride ionshave disappeared, then washed with methanol, dried in vacuo at 40° C.and then dried to constant weight over phosphorus pentoxide at ambienttemperature. 1,000 g of copolyurethane, containing 0.195milliequivalent/g of tertiary nitrogen and 1.066 meq/g of oxyethyleneunits --O--CH₂ --CH₂ --, are thus obtained.

Preparation of the Quaternised Copolyurethane

500 g of the copolyurethane prepared at the start of the presentexample, and 4 liters of methanol, are introduced into a 5 liter reactorequipped with a stirring system. 27.7 g of methyl iodide are introduced,under an argon atmosphere, the reactor is stoppered and the mixture isstirred for 20 hours at ambient temperature. The polymer is filteredoff, washed with methanol and dried to constant weight as above.

The degree of quaternisation is 77%. The polymer contains 0.150milliequivalent/g of quaternary ammonium and 0.042 milliequivalent/g ofunsalified tertiary nitrogen.

EXAMPLE 5

900 g of dimethylformamide are introduced into a 2 liter reactorequipped with a stirring system and are cooled to about 3° C. 100 g of apolyvinyl chloride of which the viscosity index is equal to 80 dl/g(measurement carried out according to Encyclopaedia of Polymer Scienceand Technology, Volume 14, page 374, 1971 edition) are then introducedslowly. The temperature of the mixture is allowed to rise to ambienttemperature and stirring is continued until the solid has completelydissolved.

80 g of the solution prepared above, and 5.33 g of a polyurethane, withtertiary amine groups (unsalified and unquaternised), obtained inaccordance with Example 1, are introduced into a 125 cm³ flask. Theweight ratio of the polyvinyl chloride to the polyurethane is 60/40 andthe concentration of the polymers in the solvent is 15.6%. The flask isshaken for 24 hours until the solid has completely dissolved. Theresulting solution is filtered and degassed and then run onto a glassplate so as to form an approximately 0.4 mm thick liquid film. This filmis dried at 50° C. under an absolute pressure of 200 mm Hg and thendetached from its support by dipping in water. The resulting material istransparent and possesses a good tear strength. Its mechanicalproperties are as follows:

tensile strength: 356 Kg/cm²

elongation at break: 84%

EXAMPLE 6

The mixture of vinyl chloride polymer/polyurethane is prepared underidentical conditions to those of Example 5, except that the polyurethaneused is the polyurethane containing 0.538 milliequivalent/g ofquaternary ammonium groups, obtained in accordance with the techniquedescribed in Example 1 (preparation of the quaternised polyurethane).

The resulting material is transparent and possesses a good tear strengthand its mechanical properties are as follows:

tensile strength: 427 Kg/cm²

elongation at break: 74%

EXAMPLE 7

The mixture of polyvinyl chloride/polyurethane is prepared underconditions identical to those of Example 5, except that the polyurethaneused is the polyurethane containing 0.599 milliequivalent/g of tertiarynitrogen (unquaternised tertiary amine groups), obtained in accordancewith the technique described in Example 3.

The resulting material is transparent and possesses a good tearstrength.

EXAMPLE 8

The mixture of vinyl chloride polymer/polyurethane is prepared underidentical conditions to those of Example 5, except that the polyurethaneused is the polyurethane, with quaternary ammonium groups, obtained inaccordance with the technique described in Example 3.

The resulting material is transparent and possesses a good tearstrength.

EXAMPLE 9

The mixture of vinyl chloride polymer/polyurethane is prepared underidentical conditions to those of Example 5, except that the polyurethaneused is the polyurethane containing 0.184 milliequivalent/g ofquaternary nitrogen (quaternary ammonium groups), obtained in accordancewith the technique described in Example 2 (preparation of quaternisedpolyurethane).

The resulting material is transparent and possesses a good tear strengthand its mechanical properties are as follows:

tensile strength: 374 Kg/cm²

elongation at break: 100%

EXAMPLE 10

The mixture of vinyl chloride polymer/polyurethane is prepared underidentical conditions to those of Example 5, except that the polyurethaneused is the polyurethane containing 0.150 milliequivalent/g ofquaternary nitrogen (quaternary ammonium groups) and 0.042milliequivalent/g of tertiary nitrogen, obtained in accordance with thetechnique described in Example 4 (preparation of quaternisedpolyurethane).

The resulting material is transparent and possesses a good tearstrength.

EXAMPLE 11

The mixture of polyvinyl chloride/polyurethane is prepared underidentical conditions to those of Example 5, except that 3.1 cm³ of a Nsolution of HCl in dimethylformamide are introduced into the solution ofthe mixture of polymers, which has the effect of salifying the tertiaryamine sites (and of converting them into tertiary ammonium groups). Thefilm obtained in accordance with the technique described in Example 5 isflexible and transparent and possesses a good tear strength.

EXAMPLE 12

The polyvinyl chloride in Examples 5 to 11 is replaced by a vinylchloride/vinyl acetate copolymer of which the units corresponding tothese two monomers are in respective proportions by weight of 85/15, andof which the viscosity index is 54 cm³ /g, measured in accordance withAFNOR Standard Specification NF T-51013, and the coefficient K (asdefined in Encyclopaedia of Polymer Science and Technology, Volume 14,pages 374-5, 1971 edition) is equal to about 46.

Similar results to those of Examples 5 to 11 are obtained, that is tosay that the resulting material (based on a mixture of vinyl chloridepolymer and of polyurethane with amine and/or quaternary ammoniumgroups), in the form of a flexible and transparent film, possesses goodmechanical properties, in particular a good tear strength.

EXAMPLE 13

The vinyl chloride polymer used is a vinyl chloride/vinyl acetate/maleicacid terpolymer. The repeat units corresponding to these three monomersare in respective proportions by weight of 84.5/14.4/1.1 (0.189 meq/g ofacid groups). This polymer has a molecular weight which is such that itsviscosity index (according to AFNOR Standard Specification NF-51013) isabout 55 cm³ /g and its coefficient K (as defined in Encyclopaedia ofPolymer Science and Technology, Volume 14, pages 374-5, 1971 edition) isequal to about 46.

The technique described in Example 5 is then repeated, the vinylchloride polymer described being replaced by this terpolymer, and eachof the unquaternised polyurethanes and each of the salified orquaternised polyurethanes described in each of Examples 1 to 4 beingused successively as the polyurethane.

This gives transparent flexible films possessing good mechanicalproperties, in particular a good tear strength.

EXAMPLE 14

405 g of dimethylformamide are introduced into a reactor equipped with astirring system, the dimethylformamide is stirred and 90 g of thepolyurethane containing 0.150 milliequivalent/g of quaternary ammoniumand 0.042 milliequivalent/g of tertiary nitrogen, obtained in accordancewith the technique described in Example 4 (preparation of quaternisedpolyurethane), and then 45 g of the terpolymer used in Example 13, areintroduced slowly. Stirring is continued until the solid has completelydissolved, the concentration of the polymers in the solvent than being25%.

A solution of 15 g heparin (in the form of the sodium salt) in 33 cm³ ofwater is prepared at the same time and this solution is poured slowlyinto 48 cm³ of diethylene glycol. The resulting homogeneous solution ispoured dropwise, in the course of one hour, into the mixture ofpolyurethane and vinyl chloride copolymer.

The resulting composition is run slowly into six liters of ethyl ether,whilst stirring vigorously, in order to precipitate the heparin-treatedpolymer. This polymer is filtered off, washed with ether and dried toconstant weight (143.7 g) in an oven, in vacuo, at 50° C., under anabsolute pressure of 200 mm Hg.

60 g of the heparin-treated composition prepared above are introducedinto a malaxator and 35 cm³ of acetone are added in small portions.Malaxation is continued until a homogeneous paste is obtained. The pastethus obtained, which contains 27% of acetone, is extruded through asector die producing a thin tube. Extrusion is carried out at 70°-80° C.under a pressure of 470 to 580 bars, the speed at which the tube leavesthe die being about 35 cm/minute. The tube is then chopped and thepieces of extruded tube are dried for three days in the verticalposition and in an ambient atmosphere, and then under an absolutepressure of 200 mm Hg at 50° C. The catheters thus prepared have anexternal diameter of 1.9 mm and a wall thickness of 0.2 mm; when broughtinto contact with freshly sampled dog's blood, they do not causecoagulation during the period of the experiment, which was one hour.

EXAMPLE 15

50 g of polyurethane with quaternary ammonium groups (prepared inaccordance with Example 2) are mixed with 50 g of polyvinyl chloride.The mixture is dissolved in 400 g of dimethylformamide at 23° C., whilststirring.

Furthermore, a solution is prepared using 20 g of heparin (in the formof the sodium salt) and 35 g of water and then 175 g of diethyleneglycol.

The heparin solution is then added to the solution of the polymermixture. A solution of a heparin-treated polymer composition, accordingto the invention, is thus obtained.

This solution is used on the one hand, for producing films, and, on theother hand, for producing a catheter.

Preparation of a Film

The solution of the heparin-treated polymer composition is run onto aglass plate so as to form a liquid film of dimensions 25 cm×30 cm×0.1cm. This is dried for 12 hours at 50° C. under an absolute pressure of200 mm Hg. It is washed with water and dried again in the same manner.

Preparation of the Catheter

A glass rod of length 25 cm and diameter 3 mm is dipped in the solutionof the heparin-treated polymer composition. It is left to drain atambient temperature for one hour and then dried at 50° C. for one hourunder an absolute pressure of 200 mm Hg. These coating operations arerepeated four times and the rod is then finally dried for 12 hours at50° C. under a reduced pressure of 200 mm Hg (absolute pressure).

When brought into contact with freshly sampled dog's blood, neither thefilm nor the catheter causes coagulation of the blood during the periodof the experiment (one hour).

EXAMPLE 16

Example 15 is repeated, replacing the polyvinyl chloride on the one handby a vinyl chloride/vinyl acetate copolymer, such as that used inExample 12, and on the other hand by a terpolymer such as that used inExample 13.

Films and catheters which do not cause coagulation of the blood areobtained in the same manner.

EXAMPLE 17 17(a)--Preparation of a macrodiisocyanate from a polyoxypropylene glycol with tertiary amine groups salified by HCl

385.7 g of a salified polyether, prepared according to example 1, areintroduced under a nitrogen atmosphere into a 2000 cm³ reactor equippedwith a stirring system and a reflux condenser. The salified polyether isdehydrated for one hour, at 100° C., under an absolute pressure of 1mmHg. Then the temperature is lowered to 80° C. and atmospheric pressureis re-established by introducing nitrogen.

188.2 g of bis(-4 isocyanato cyclohexyl)methane are added, in the moltenstate and all at once, to the salified polyether. The reaction mixtureis kept at 80° C. for 50 hours, whilst stirring. The resultingmacrodiisocyanate is cooled and dissolved in 325 cm³ ofdimethylformamide.

17(b)--Preparation of a macrodiisocyanate from a polyoxyethylene glycol

601 g of a polyoxyethylene glycol (marketed under the trademark CARBOWAX1,500), having a molecular weight of 1,500, are introduced in anapparatus identical to that above and in the same manner. The glycol ismelted and dehydrated at 100° C. under an absolute pressure of 1 mmHg.Then atmospheric pressure is re-established by introducing nitrogen andthe temperature is lowered to 80° C.

220.1 g of bis(-4 isocyanato cyclohexyl)methane are added, in the moltenstate and all at once, to the polyether. The reaction mixture is kept at80° C. for 8 hours, whilst stirring. The resulting macrodiisocyanate iscooled and dissolved in 465 cm³ of dimethylformamide.

17(c)--Preparation of a polyurethane with salified tertiary amine groups

3063 g of dimethylformamide and 32.97 g of 1-2diaminopropane areintroduced under a nitrogen atmosphere in a 5,000 cm³ reactor equippedwith a stirring system and a reflux condenser.

This solution being at room temperature, 80% of a mixture of 863.1 g ofa 65% strength solution, in dimethylformamide, of the macrodiisocyanateprepared in accordance with 17(a), and of 440.64 g of a 65% strengthsolution, in dimethylformamide, of the macrodiisocyanate prepared inaccordance with 17(b), is then run in, in the course of 15 minutes. Therest of the mixture of the two macrodiisocyanates is added for 90minutes. The reaction mixture is then kept under nitrogen atmosphere for15 hours, whilst stirring.

1/3 of the polyurethane solution thus obtained is poured slowly, whilststirring, into 30 liters of water containing 600 g of sodium chloride,at 5° C., in order to precipitate the polymer. The latter is filteredoff, washed with water until the chloride ions have disappeared and thendried in vacuo at 30° C.

211 g of copolyurethane, containing 0.204 milliequivalent/g of salifiedtertiary amine and 10.61 milliequivalent/g of oxyethylene units, arethus obtained.

17(d)--Preparation of a polyurethane with tertiary amine groups

2/3 of the solution of copolyurethane prepared in 17(c) are pouredslowly into 60 liters of water containing 1,200 g of sodium chloride and240 g of sodium hydroxyde, at 5° C., in order to precipitate thepolyether and to liberate the amine groups. The product is dried bylyophilisation.

590 g of copolyurethane, containing 0.206 meq/g of tertiary aminegroups, are thus obtained.

17(e)--Preparation of the quaternised polyurethane

188 g of unquaternised polyurethane prepared in 17(d) are quaternised inaccordance with the technique described in example 4, methanol beingreplaced by acetone.

183 g of dried polymer, containing 0.2 meq/g of quaternary ammonium, arethus obtained.

EXAMPLE 18

12.5 g of polyurethane with quaternary ammonium groups (prepared inaccordance with example 17(e) are mixed with 12.5 g of polyvinylchloride described in example 5. The mixture is dissolved in 290 cm³ ofdimethylformamide, whilst stirring, at 23° C. for 3 hours and then forone hour at 80° C. The resulting solution is filtered and degassed andthen run onto a glass plate so as to form an approximately 1 mm thickliquid film. This film is dried at 50° C. under an absolute pressure of200 mmHg and then detached from its support by dipping in water. Theresulting material is transparent and possesses a good tear strength.Its mechanical properties are as follows:

tensile strength: 370 kg/cm²

elongation at break: 270%

EXAMPLE 19

A film from a solution of polyvinyl chloride and polyurethane withtertiary amine groups (obtained in accordance with example 17(d) isprepared under identical conditions to those of example 18. Theresulting material is transparent and possesses a good tear strength:

tensile strength: 310 kg/cm²

elongation at break: 230%

EXAMPLE 20

A film is prepared under identical conditions to those of example 18from a solution of polyvinyl chloride and polyurethane with tertiaryamine groups, salified by hydrochloric acid (obtained in example 17(c)).The resulting film is transparent and possesses a good tear strength:

tensile strength: 300 kg/cm²

elongation at break: 195%

EXAMPLE 21

The polyvinyl chloride in examples 18 to 20 is replaced by the vinylchloride/vinyl acetate/maleic acid terpolymer, described in example 13.

Similar results to those of examples 18 to 20 are obtained, that is tosay that the resulting materials (with amine and/or ammonium groups,prepared in accordance with example 17) in the form of flexible andtransparent films, possesses good mechanical properties, in particular agood tear strength.

EXAMPLE 22

12.5 g of polyurethane with quaternary ammonium groups (prepared inaccordance with example 17(e) are mixed with 12.5 g of vinylchloride/vinyl acetate/maleic acid terpolymer described in example 13.The mixture is dissolved in 100 g of dimethylformamide at 100° C. for 2hours, whilst stirring.

Furthermore, a solution is prepared using 5 g of heparin (in the form ofthe sodium salt) and 8.75 g of water and then 43.8 g of diethyleneglycol.

The heparin solution is then added to the solution of the polymermixture which is at room temperature. A solution of a heparin-treatedpolymer composition, according to the invention, is thus obtained.

This solution is used for producing a film.

Preparation of a Film

The solution of the heparin-treated polymer composition is run onto aglass plate so as to form a liquid film of dimensions 20 cm×30 cm×0.1cm. This is dried for 24 hours at 50° C. under an absolute pressure of200 mmHg. It is washed with ether and dried again in the same manner.The resulting film contains 16.6% of heparin.

Coagulation Test with the Resulting Film

Membranes with a diameter of 12 cm are cut in the heparinated filmobtained above. After folding these membranes are put into glass conesand they match with the shape of the latter. Then membrane-cones arefilled with physiological liquid (water with 9 g/l of NaCl) and thetemperature of the latter is kept at 37° C. In each cone thephysiological liquid is replaced by 2 cm³ of freshly sampled humanvenous blood. This blood coagulates after a contact of 5 minutes and 30seconds with the glass. No coagulation takes place after a contact of 90minutes with the heparinated membranes.

EXAMPLE 23

In example 22 the terpolymer is replaced by the polyvinyl chloridedescribed in example 5. Films are obtained in the same manner and nocoagulation takes place with such films.

EXAMPLE 24

The film prepared in example 18, of which the swelling capacity is 15%in water and is 40% in a mixture of ethanol/water (50%--50% by volume),is immersed in 250 cm³ of a solution water/ethanol (50%--50% by volume)of 3% by weight of heparin (in the form of sodium salt), for 16hours, at50° C. The film is then washed with water and dried at 50° C., for 10hours, under 200 mmHg.

The resulting film contains about 2% by weight of heparin.

EXAMPLE 25

90 g of dimethylformamide are introduced in a reactor equipped with astirring system, and 10 g of polyurethane containing 0.189 meq/g oftertiary nitrogen groups (prepared in accordance with example 2) areintroduced slowly in the reactor. After dissolution, it is run into 2.55cm³ of a N solution of hydrochloric acid in order to salify thepolyurethane and then 5 g of the terpolymere of example 13 are added.The mixture is stirred until it has completely dissolved.

A solution is prepared, containing 1.67 g of heparin (in the form of itssodium salt), 2.9 cm³ of water and 14.55 g of diethylene glycol. Thissolution is added in the course of 30 minutes to the mixture of salifiedpolyurethane and of the terpolymer of vinyl chloride.

The heparinated solution is filtered, degassed and then run onto a glassplate so as to form a liquid film of dimensions 25 cm×30 cm×0.1 cm. Thisis dried at 50° C., for 24 hours, under an absolute pressure of 200mmHg. The resulting film is homogeneous, flexible and transparent.

No coagulation takes place with this film in course of 90 minutes, underthe same conditions as those of example 22.

What is claimed is:
 1. Polymer compositions, useful especially in themedical field, consisting of a mixture of vinyl chloride polymer and apolyether--urethane with tertiary amine and/or ammonium groups andheparin, with the porportion of the polyether--urethane being from 1 to99% by weight, relative to the total mixture.
 2. The polymercompositions according to claim 1 wherein the ammonium groups arequaternary ammonium groups.
 3. Composition according to claim 1,characterised in the at the proportions of polyurethane is between 20and 60% by weight.
 4. Compositions according to claim 1 characterized inthat the vinyl chloride polymer comprises at least 60% by weight ofchloroethylene units.
 5. Compositions according to claim 1 characterisedin that the vinyl chloride polymer is a vinyl chloride homopolymer or avinyl chloride/vinyl ester copolymer.
 6. Compositions according to claim1, characterised in that the polyether-urethanes are polyurethanescomprising oxyalkylene groups.
 7. Compositions according to claim 1characterised in that they satisfy: m+p≧0.5 and p+q≧n-2.5, the lettersn, m, p and q respectively denoting:n: the number of milliequivalents ofoxethylene units-- O--CH₂ --CH₂ --per 100 g of polyurethane, m: thenumber of milliequivalents of tertiary amine groups, which may or maynot be salified, per 100 g of polyurethane, p: the number ofmilliequivalents of quaternary ammonium groups per 100 q ofpolyurethane, and q: the number of milliequivalent of ionic groups per100 g of vinyl chloride polymer.
 8. Compositions according to claim 1,characterised in that the polyether-urethanes comprise a plurality ofrepeat units of the formula:

    --A--NH--CO--O--B--O--CO--NH--                             (I)

and of repeat units of the formula:

    --A--NH--CO--Z--NH--                                       (II)

in which formulae: B is the divalent radical in macrodiol of thepolyether type, of the formula: HO--B--OH, A is the divalent radical inan aliphatic and/or cycloaliphatic and/or aromatic diisocyanate of theformula: O═C═N--A--N═C═O, and Z is a valence bond or a divalent radicalsuch as: --NH--NH--CO--, --NH--CH₂ --CO--NH--NH--CO--, --NR₂ --D--NR₃--CO or --O--M--O--CO--; R₂, R₃ and M are such that NHR₂ --D--NHR₃ is aprimary or secondary diamine and HO--M--OH is a diol.
 9. Compositionsaccording to claim 1 characterised in that the proportion of heparin isbetween 1 and 15%, relative to the polymers.
 10. Compositions accordingto claim 7, characterised in that p₁ -q₁ >0 and in that the proportionof herparin is between 0.5 and 35% by weight relative to all thepolymers, p₁ being the product of p multiplied by the percentage byweight of the polyurethane in the mixture, divided by 100, and q₁ beingthe product of q multiplied by the percentage by weight of the of thevinyl chloride polymer, with ionic sites, in the mixture, divided by100.